This application is a continuing application of co-pending International patent application PCT/US99/13744, filed Jun. 17, 1999, designating the United States, which claims priority from United States provisional patent application No. 60/090,094, filed Jun. 19, 1998.
The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention and methods for screening compounds for anti-HIV activity.
The human immunodeficiency virus (xe2x80x9cHIVxe2x80x9d) is the causative agent for acquired immunodeficiency syndrome (xe2x80x9cAIDSxe2x80x9d)xe2x80x94a disease characterized by the destruction of the immune system, particularly of CD4+ T-cells, with attendant susceptibility to opportunistic infectionsxe2x80x94and its precursor AIDS-related complex (xe2x80x9cARdfgCxe2x80x9d)xe2x80x94a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.
As in the case of several other retroviruses, HIV encodes the production of a protease which carries out post-translational cleavage of precursor polypeptides in a process necessary for the formation of infectious virions (S. Crawford et al., xe2x80x9cA Deletion Mutation in the 5xe2x80x2 Part of the pol Gene of Moloney Murine Leukemia Virus Blocks Proteolytic Processing of the gag and pol Polyproteinsxe2x80x9d, J. Virol., 53, p. 899 (1985)). These gene products include pol, which encodes the virion RNA-dependent DNA polymerase (reverse transcriptase), an endonuclease, HIV protease, and gag, which encodes the core-proteins of the virion (H. Toh et al., xe2x80x9cClose Structural Resemblance Between Putative Polymerase of a Drosophila Transposable Genetic Element 17.6 and pol gene product of Moloney Murine Leukemia Virusxe2x80x9d, EMBO J., 4, p. 1267 (1985); L. H. Pearl et al., xe2x80x9cA Structural Model for the Retroviral Proteasesxe2x80x9d, Nature, pp. 329-351 (1987); M.D. Power et al., xe2x80x9cNucleotide Sequence of SRV-1, a Type D Simian Acquired Immune Deficiency Syndrome Retrovirusxe2x80x9d, Science, 231, p. 1567 (1986)).
A number of synthetic anti-viral agents have been designed to target various stages in the replication cycle of HIV. These agents include compounds which block viral binding to CD4+ T-lymphocytes (for example, soluble CD4), and compounds which interfere with viral replication by inhibiting viral reverse transcriptase (for example, didanosine and zidovudine (AZT)) and inhibit integration of viral DNA into cellular DNA (M. S. Hirsh and R. T. D""Aqulia, xe2x80x9cTherapy for Human Immunodeficiency Virus Infectionxe2x80x9d, New Eng. J. Med., 328, p. 1686 (1993)). However, such agents, which are directed primarily to early stages of viral replication, do not prevent the production of infectious virions in chronically infected cells. Furthermore, administration of some of these agents in effective amounts has led to cell-toxicity and unwanted side effects, such as anemia and bone marrow suppression.
More recently, the focus of anti-viral drug design has been to create compounds which inhibit the formation of infectious virions by interfering with the processing of viral polyprotein precursors. Processing of these precursor proteins requires the action of virus-encoded proteases which are essential for replication (Kohl, N. E. et al. xe2x80x9cActive HIV Protease is Required for Viral Infectivityxe2x80x9d Proc. Natl. Acad. Sci. USA, 85, p. 4686 (1988)). The anti-viral potential of HIV protease inhibition has been demonstrated using peptidal inhibitors. Such peptidal compounds, however, are typically large and complex molecules that tend to exhibit poor bioavailability and are not generally consistent with oral administration.
Accordingly, the need still exists for compounds that can effectively inhibit the action of viral proteases, for use as agents for preventing and treating chronic and acute viral infections.
The present invention provides a novel class of compounds, and pharmaceutically acceptable derivatives thereof, that are useful as inhibitors of aspartyl proteases, in particular, HIV aspartyl protease. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, antibiotics, immunomodulators or vaccines, for the treatment or prophylaxis of viral infection.
According to a preferred embodiment, the compounds of this invention are capable of inhibiting HIV viral replication in human CD4+ T-cells. These compounds are useful as therapeutic and prophylactic agents to treat or prevent infection by HIV-1 and related viruses which may result in a symptomatic infection, AIDS-related complex (xe2x80x9cARCxe2x80x9d), acquired immunodeficiency syndrome (xe2x80x9cAIDSxe2x80x9d), or similar disease of the immune system.
It is a principal object of this invention to provide a novel class of sulfonamides which are aspartyl protease inhibitors, and particularly, HIV aspartyl protease inhibitors. The novel sulfonamides of this invention are those of formula I: 
wherein:
A is selected from H; Ht; xe2x80x94R1xe2x80x94Ht; xe2x80x94R1xe2x80x94Cxe2x80x94C6 alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, C1-C4 alkoxy, Ht, xe2x80x94Oxe2x80x94Ht, xe2x80x94NR1xe2x80x94COxe2x80x94N(R2)2 or xe2x80x94COxe2x80x94N(R2) 2; xe2x80x94R1xe2x80x94C2xe2x80x94C6 alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C1xe2x80x94C4 alkoxy, Ht, xe2x80x94Oxe2x80x94Ht, xe2x80x94NR2xe2x80x94COxe2x80x94N(R2)2 or xe2x80x94COxe2x80x94N(R2)2; or R7;
each R1 is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94S(O)2, xe2x80x94NR2xe2x80x94S(O)2, xe2x80x94NR2xe2x80x94C(O)xe2x80x94 or xe2x80x94NR2xe2x80x94C(O)xe2x80x94C(O)xe2x80x94;
each Ht is independently selected from C3xe2x80x94Cxe2x80x94cycloalkyl; C5xe2x80x94C7 cycloalkenyl; C6-C14 aryl; or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R2), O, S and S(O)n; wherein said aryl or said heterocycle is optionally fused to Q; and wherein any member of said Ht is optionally substituted with one or more substituents independently selected from oxo, xe2x80x94OR2, SR2, xe2x80x94Rxe2x80x94, xe2x80x94N(R2) (R2), xe2x80x94R2xe2x80x94OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N (R2)2, xe2x80x94S(O)2xe2x80x94N (R2)2, xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94R2, xe2x80x94C(O)xe2x80x94R2, xe2x80x94S(O)nxe2x80x94R2, xe2x80x94OCF3, xe2x80x94S(O)nxe2x80x94Q, methylenedioxy, xe2x80x94N(R2)xe2x80x94S(O)2(R2) halo, xe2x80x94CF3, xe2x80x94NO2, Q, xe2x80x94OQ, xe2x80x94OR7, xe2x80x94SR7, xe2x80x94R7, xe2x80x94N(R2) (R7) or xe2x80x94N(R7)2;
each R2 is independently selected from H, or C1xe2x80x94C6 alkyl optionally substituted with Q or R10;
B, when present, is xe2x80x94N(R2)xe2x80x94C(R3)2xe2x80x94C(O)xe2x80x94;
each x is independently 0 or 1;
each R3 is independently selected from H, Ht, C1xe2x80x94C6 alkyl, C2xe2x80x94C6 alkenyl, C3xe2x80x94C6 cycloalkyl or C5xe2x80x94C6 cycloalkenyl; wherein any member of said R3, except H, is optionally substituted with one or more substituents selected from xe2x80x94OR2, xe2x80x94C(O)xe2x80x94NHxe2x80x94R2, xe2x80x94S(O)xe2x80x94N (R2)(R2) Ht, xe2x80x94CN, xe2x80x94SR2, xe2x80x94CO2R2, NR2xe2x80x94C(O)xe2x80x94R2;
each n is independently 1 or 2;
G, when present, is selected from H, R7 or C1xe2x80x94C4 alkyl, or, when G is C1-C4 alkyl, G and R7 are bound to one another either directly or through a C1xe2x80x94C3 linker to form a heterocyclic ring; or
when G is not present (i.e., when x in (G)x is 0), then the nitrogen to which G is attached is bound directly to the R7 group in xe2x80x94OR7 with the concomitant displacement of one xe2x80x94ZM group from R7;
D is selected from Q; C1xe2x80x94C6 alkyl, which is optionally substituted with one or more groups selected from C3xe2x80x94C6 cycloalkyl, xe2x80x94OR, xe2x80x94Sxe2x80x94Ht, xe2x80x94R3, xe2x80x94Oxe2x80x94Q or Q; C2xe2x80x94C4 alkenyl, which is optionally substituted with one or more groups selected from xe2x80x94OR2, xe2x80x94Sxe2x80x94Ht, xe2x80x94R3, xe2x80x94Oxe2x80x94Q or Q; C3xe2x80x94C6 cycloalkyl, which is optionally substituted with or fused to Q; or C5xe2x80x94C6 cycloalkenyl, which is optionally substituted with or fused to Q;
each Q is independently selected from a 3-7 membered saturated, partially saturated or unsaturated carbocyclic ring system; or a 5-7 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from O, N, S, S(O)n, or N(R2); wherein Q is optionally substituted with one or more groups selected from oxo, xe2x80x94OR2, xe2x80x94R2, xe2x80x94SO2xe2x80x94R2, xe2x80x94SO2xe2x80x94N(R2)2, xe2x80x94N(R2)2, xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94R2, xe2x80x94Rxe2x80x94OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)2, halo or xe2x80x94CF3;
Dxe2x80x2 is selected from xe2x80x94OR10, xe2x80x94Nxe2x95x90R10 or xe2x80x94N(R10)xe2x80x94R1xe2x80x94R3;
E is selected from Ht; Oxe2x80x94Ht; Htxe2x80x94Ht; xe2x80x94Oxe2x80x94R3;
xe2x80x94N(R2)(R3); C1xe2x80x94C6 alkyl, which is optionally substituted with one or more groups selected from R4 or Ht; C2xe2x80x94C6 alkenyl, which is optionally substituted with one or more groups selected from R4 or Ht; C3xe2x80x94C6 saturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht; or C3xe2x80x94C6 unsaturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht;
each R4 is independently selected from xe2x80x94ORxe2x80x94, xe2x80x94SRxe2x80x94, xe2x80x94SORxe2x80x94, xe2x80x94SO2R2, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94NHR2, xe2x80x94C(O)xe2x80x94N(R2)2, xe2x80x94C(O)xe2x80x94NR2(OR2), xe2x80x94S(O)2xe2x80x94NHR2, halo, xe2x80x94NR2xe2x80x94C(O)xe2x80x94R2, xe2x80x94N(R2)2 or xe2x80x94CN;
each R7 is independently selected from hydrogen, 
wherein each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, xe2x80x94N(R2)4, C2xe2x80x94C12xe2x80x94alkyl, C2xe2x80x94C12-alkenyl, or xe2x80x94R6; wherein 1 to 4 xe2x80x94CH2 radicals of the alkyl or alkenyl group, other than the xe2x80x94CH2 that is bound to Z, is optionally replaced by a heteroatom group selected from O, S, S(O), S (O2), or N(R2); and wherein any hydrogen in said alkyl, alkenyl or Re is optionally replaced with a substituent selected from oxo, xe2x80x94ORxe2x80x94, xe2x80x94R2, N(R2)2, N(R2)3, Rxe2x80x94OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)2, S(O)2xe2x80x94N(R2)2, N(R2)xe2x80x94C(O)xe2x80x94R2, C(O)R2, xe2x80x94S(O)nxe2x80x94R2, OCF3, xe2x80x94S(O)nxe2x80x94R6, N (R2)xe2x80x94S(O)2(R2), halo, xe2x80x94CF3, or xe2x80x94NO2;
Mxe2x80x2 is H, C1-C12-alkyl, C2-C12-alkenyl, or xe2x80x94R6; wherein 1 to 4 xe2x80x94CH2 radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from O, S, S(O), S(O2), or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, xe2x80x94OR2, xe2x80x94R2, xe2x80x94N(R2)2, N(R2)3, xe2x80x94Rxe2x80x94OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)2, xe2x80x94S(O)2xe2x80x94N (R2)2, xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94R2, xe2x80x94C(O)R2, xe2x80x94S(O)nxe2x80x94R2, xe2x80x94OCF3, xe2x80x94S(O)nxe2x80x94R6, xe2x80x94N(R2)xe2x80x94S(O)2(R2), halo, xe2x80x94CF3, or xe2x80x94NO2;
Z is O, S, N(R2)2, or, when M is not present, H.
Y is P or S;
X is O or S; and
R9 is C(R2)2, O or N(R2); and wherein when Y is S, Z is not S; and
R6 is a 5-6 membered saturated, partially saturated or unsaturated carbocyclic or heterocyclic ring system, or an 8-10 membered saturated, partially saturated or unsaturated bicyclic ring system; wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from O, N, S, S(O)n or N(R2); and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, C1-C4 alkyl, xe2x80x94Oxe2x80x94C1-C4 alkyl or xe2x80x94Oxe2x80x94C(O)xe2x80x94C1-C4 alkyl;
R10 is selected from C1-C8 alkyl, C2-C6 alkenyl, C6-C14 aryl or Ht, wherein R10 optionally contains up to three substituents independently selected from xe2x80x94R3, xe2x80x94CN, xe2x80x94SR5, xe2x80x94SOR5, xe2x80x94SO2R5, xe2x80x94SRxe2x80x94NR5xe2x80x94C(O) R6, xe2x80x94NR5xe2x80x94(SO2) R5, xe2x80x94C(O)N(R5)2, xe2x80x94C(S)N(R5)2, xe2x80x94S(O)2N(R5)2, xe2x80x94C(O)R6, xe2x80x94C(S)R6, xe2x80x94N(R5)2,xe2x80x94NR5 xe2x80x94C(O)R5, xe2x80x94NR5xe2x80x94C(O)OR5, xe2x80x94NR5xe2x80x94C(O)N(R5)2, xe2x80x94NR5xe2x80x94C(S)R5, xe2x80x94NR5xe2x80x94C(S)OR, xe2x80x94NR5xe2x80x94C(S)N(R5)2, xe2x80x94NR5xe2x80x94C[xe2x95x90N(R5)]xe2x80x94N(R5)2, xe2x80x94NHxe2x80x94C[xe2x95x90Nxe2x80x94NO2]xe2x80x94NH2, xe2x80x94NHxe2x80x94C[xe2x95x90Nxe2x80x94NO2]xe2x80x94OR5, xe2x80x94N(R8)2xe2x80x94C(O)R8, xe2x80x94OC(O)R6, xe2x80x94OC(O)N(R5)2, xe2x80x94OC(S)N(R5)2, wherein any one of the xe2x80x94CH2 groups of said alkyl or alkenyl chains of R10 may be optionally replaced by O, S, SO, SO2, C(O) or NR5; wherein each R5 is independently selected from hydrogen, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or Ht, wherein each R5, except for hydrogen, is optionally substituted with xe2x80x94CF3, xe2x80x94PO3R3, azido or halo.
It is also an object of this invention to provide pharmaceutical compositions comprising the sulfonamides of formula (I) and methods for their use as inhibitors of HIV aspartyl protease.
In order that the invention herein described may be more fully understood, the following detailed description is set forth. In the description, the following terms are employed herein:
Unless expressly stated to the contrary, the terms xe2x80x9cxe2x80x94SO2xe2x80x94xe2x80x9d and xe2x80x9cxe2x80x94S(O)2xe2x80x94xe2x80x9d as used herein refer to a sulfone or sulfone derivative (i.e., both appended groups linked to the S), and not a sulfinate ester.
For the compounds of formula I, and intermediates thereof, the stereochemistry of OR7 is defined relative to D on the adjacent carbon atom, when the molecule is drawn in an extended zig-zag representation (such as that drawn for compound of formula I). If both OR7 and D reside on the same side of the plane defined by the extended backbone of the compound, the stereochemistry of OR7 will be referred to as xe2x80x9csynxe2x80x9d. If OR7 and D reside on opposite sides of that plane, the stereochemistry of OR7 will be referred to as xe2x80x9cantixe2x80x9d.
The term xe2x80x9calkylxe2x80x9d, alone or in combination with any other term, refers to a straight-chain or branch-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms, or where no number is specified, preferably from 1 to about 10 and more preferably from 1 to about 8 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, n-hexyl and the like.
The term xe2x80x9calkenylxe2x80x9d alone or in combination with any other term, refers to a straight-chain or branched-chain mono- or poly-unsaturated aliphatic hydrocarbon radical containing the specified number of carbon atoms, or where no number is specified, preferably from 2 to about 18 carbon atoms and more preferably, from 2 to about 8 carbon atoms. Examples of alkenyl radicals include, but are not limited to, ethenyl, propenyl, isopropenyl, 1,4-butadienyl, pentenyl and the like.
The term xe2x80x9calkoxyxe2x80x9d refers to an alkyl ether radical, wherein the term xe2x80x9calkylxe2x80x9d is defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. The term xe2x80x9carylxe2x80x9d alone or in combination with any other term, refers to a carbocyclic aromatic radical (such as phenyl or naphthyl) containing the specified number of carbon atoms, preferably from 6-14 carbon atoms, and more preferably from 6-10 carbon atoms, optionally substituted with one or more substituents selected from C1-6 alkoxy, (for example methoxy), nitro, halogen, (for example chloro), amino, carboxylate and hydroxy. Examples of aryl radicals include, but are not limited to phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, anthracenyl and the like.
The term xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d refers to a stable 3-7 membered monocyclic heterocyclic ring or 8-11 membered bicyclic heterocyclcic ring which is either saturated or unsaturated, and which may be optionally benzofused if monocyclic. Each heterocycle consists of one or more carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. As used herein, the terms xe2x80x9cnitrogen and sulfur heteroatomsxe2x80x9d include any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. A heterocyclyl radical may be attached at any endocyclic carbon or heteroatom which results in the creation of a stable structure. Preferred heterocycles include 5-7 membered monocyclic heterocycles and 8-10 membered bicyclic heterocycles. Examples of such groups include imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl, isoqinolyl, indolyl, indazolyl, indazolinolyl, perhydropyridazyl, pyridazyl, pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, pyranyl, pyrazolinyl, piperazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl, carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinyl sulfone, oxazolyl, benzoxazolyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, isoxozolyl, isothiazolyl, furazanyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thiadiazoyl, dioxolyl, dioxinyl, oxathiolyl, benzodioxolyl, c3 athiolyl, thiophenyl, tetrahydrothiophenyl, sulfolanyl, dioxanyl, dioxolanyl, tetahydrofurodihydrofuranyl, tetrahydropyranodihydrofuranyl, dihydropyranyl, tetradyrofurofuranyl and tetrahydropyranofuranyl.
The term xe2x80x9cpharmaceutically effective amountxe2x80x9d refers to an amount effective in treating a virus infection, for example an HIV infection, in a patient either as monotherapy or in combination with other agents. The term xe2x80x9ctreatingxe2x80x9d as used herein refers to the alleviation of symptoms of a particular disorder in a patient or the improvement of an ascertainable measurement associated with a particular disorder. The term xe2x80x9cprophylactically effective amountxe2x80x9d refers to an amount effective in preventing a virus infection, for example an HIV infection, in a patient. As used herein, the term xe2x80x9cpatientxe2x80x9d refers to a mammal, including a human.
The terms xe2x80x9cHIV proteasexe2x80x9d and xe2x80x9cHIV aspartyl proteasexe2x80x9d are used interchangeably and refer to the aspartyl protease encoded by the human immunodeficiency virus type 1 or 2. In a preferred embodiment of this invention, these terms refer to the human immunodeficiency virus type 1 asparryl protease.
The term xe2x80x9cthiocarbamatesxe2x80x9d refers to compounds containing the functional group Nxe2x80x94SO2xe2x80x94O.
Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term xe2x80x9cstablexe2x80x9d, as used herein, refers to compounds which possess stability sufficient to allow manufacture and administration to a mammal by methods known in the art. Typically, such compounds are stable at a temperature of 40xc2x0 C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. The basic nitrogen can be quaternized with any agents known to those of ordinary skill in the art including, for example, lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides including benzyl and phenethyl bromides.
Water or oil-soluble or dispersible products may be obtained by such quaternlzation.
The novel sulfonamides of this invention are those of formula I: 
wherein:
A is selected from H; Ht; xe2x80x94R1xe2x80x94Ht; xe2x80x94R1-C1-C6 alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, C1-C4 alkoxy, Ht, xe2x80x94Oxe2x80x94Ht, xe2x80x94NR2xe2x80x94COxe2x80x94N(R2) or xe2x80x94COxe2x80x94N(R2)2; xe2x80x94R1-C1-C6 alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C1-C4 alkoxy, Ht, xe2x80x94Oxe2x80x94Ht, xe2x80x94NR2xe2x80x94COxe2x80x94N(R2)2 or xe2x80x94COxe2x80x94N(R2)2; or R7;
each R1 is independently selected from xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C (O)xe2x80x94, xe2x80x94Oxe2x80x94S(O)2, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94 or xe2x80x94NR2xe2x80x94C(O)xe2x80x94C(O)xe2x80x94;
each Ht is independently selected from C3-C7 cycloalkyl; C3-C7, cycloalkenyl; C6-C14 aryl; or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R2), O, S and S(O)n; wherein said aryl or said heterocycle is optionally fused to Q; and wherein any member of said Ht is optionally substituted with one or more substituents independently selected from oxo, xe2x80x94OR2, SR2, xe2x80x94R2, xe2x80x94N(R2)(R2), xe2x80x94R2xe2x80x94OH, xe2x80x94CN, xe2x80x94CO2xe2x80x94R2, xe2x80x94C(O)xe2x80x94N (R2)2, xe2x80x94S(O)2xe2x80x94N(R2)2, xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94R2, xe2x80x94C(O)xe2x80x94R2, xe2x80x94S(O)nxe2x80x94R2, xe2x80x94OCF3, xe2x80x94S(O)nxe2x80x94Q, methylenedioxy, xe2x80x94N(R2)xe2x80x94S(O)2 (R2), halo, xe2x80x94CF3, xe2x80x94NO2, Q, xe2x80x94OQ, xe2x80x94OR7, xe2x80x94SR7, xe2x80x94R7, xe2x80x94N(R2)(R7) or xe2x80x94N(R7)2;
each R2 is independently selected from H, or C1-C6 alkyl optionally substituted with Q or R10;
B, when present, is xe2x80x94N(R2)xe2x80x94C(R3)2xe2x80x94C(O)xe2x80x94;
each x is independently 0 or 1;
each R3 is independently selected from H, Ht, C1xe2x80x94C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl or C5-C6 cycloalkenyl; wherein any member of said R3, except H, is optionally substituted with one or more substituents selected from xe2x80x94OR2, xe2x80x94C(O)xe2x80x94NHxe2x80x94R2, xe2x80x94S(O)nxe2x80x94N(R2)(R2), Ht, xe2x80x94NSR2, xe2x80x94CO2R2, NR2xe2x80x94C(O)xe2x80x94R 2;
each n is independently 1 or 2;
G, when present, is selected from H, R7 or C1-C4 alkyl, or, when G is C1-C4 alkyl, G and R7 are bound to one another either directly or through a C1-C3 linker to form a heterocyclic ring; or
when G is not present (i.e., when x in (G)x is 0), then the nitrogen to which G is attached is bound directly to the R group in xe2x80x94OR7 with the concomitant displacement of one xe2x80x94ZM group from R7;
D is selected from Q; C1-C6 alkyl, which is optionally substituted with one or more groups selected from C3-C6 cycloalkyl, xe2x80x94OR2, xe2x80x94Sxe2x80x94Ht, xe2x80x94R3, xe2x80x94Oxe2x80x94Q or Q; C2-C4 alkenyl, which is optionally substituted with one or more groups selected from xe2x80x94OR2, xe2x80x94Sxe2x80x94Ht, xe2x80x94R3, xe2x80x94Oxe2x80x94Q or Q, C3-C6 cycloalkyl, which is optionally substituted with or fused to Q; or C5-C6 cycloalkenyl, which is optionally substituted with or fused to Q;
each Q is independently selected from a 3-7 membered saturated, partially saturated or unsaturated carbocyclic ring system; or a 5-7 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from O, N, S, S(O)n, or N(R2); wherein Q is optionally substituted with one or more groups selected from oxc, xe2x80x94OR2, xe2x80x94R2, xe2x80x94SO2R2, xe2x80x94SO2xe2x80x94N(R2)2, xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94R2, xe2x80x94R2xe2x80x94OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)2, halo or xe2x80x94CF3;
Dxe2x80x2 is selected from xe2x80x94OR10, xe2x80x94Nxe2x95x90R10 or xe2x80x94N(R10)xe2x80x94R1xe2x80x94R3;
E is selected from Ht; Oxe2x80x94Ht; Htxe2x80x94Ht; xe2x80x94Oxe2x80x94R3; xe2x80x94N(R2)(R3); C1-C6 alkyl, which is optionally substituted with one or more groups selected from R4 or Ht; C2-C6 alkenyl, which is optionally substituted with one or more groups selected from R4 or Ht; C3-C6 saturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht; or C5-C6 unsaturated carbocycle, which is optionally substituted with one or more groups selected from R4 or Ht;
each R4 is independently selected from xe2x80x94OR2, xe2x80x94SR2, xe2x80x94SOR2, xe2x80x94SO2R2, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94NHR2, xe2x80x94C(O)xe2x80x94N(R2)2, xe2x80x94C(O)xe2x80x94NR2xe2x80x94(OR2), xe2x80x94S(O)2xe2x80x94NHR2, halo, xe2x80x94NR2xe2x80x94C(O)xe2x80x94R2, xe2x80x94N(R2)2 or xe2x80x94CN;
each R7 is independently selected from hydrogen, 
wherein each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, xe2x80x94N(R2)4, C2-C12-alkyl, C2-C2-alkenyl, or xe2x80x94R6; wherein 1 to 4 xe2x80x94CH2 radicals of the alkyl or alkenyl group, other than the xe2x80x94CH2 that is bound to Z, is optionally replaced by a heteroatom group selected from O, S, S(O), S(O2), or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, xe2x80x94OR2, xe2x80x94R2, N(R2)2, N(R2)3, R2OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)2, S(O)2xe2x80x94N(R)2, N(R2)xe2x80x94C(O)xe2x80x94R2, C(O)R2, xe2x80x94S(O)nxe2x80x94R2, OCF3, xe2x80x94S(O)nxe2x80x94R6, N(R2)xe2x80x94S(O)2 (R2), halo, xe2x80x94CF3, or xe2x80x94NO2;
Mxe2x80x2 is H, C1-C12-alkyl, C2-C12-alkenyl, or xe2x80x94R6; wherein 1 to 4 xe2x80x94CH2 radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from O, S, S(O), S(O2), or N(R2); and wherein any hydrogen in said alkyl, alkenyl or R6 is optionally replaced with a substituent selected from oxo, xe2x80x94OR2, R2, xe2x80x94N(R2)2, N(R2)3, xe2x80x94R2OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)2, xe2x80x94S(O)2xe2x80x94N(R2)2, xe2x80x94N (R2)xe2x80x94C(O)xe2x80x94R2, xe2x80x94C(O)R2, xe2x80x94S(O)nxe2x80x94R2, xe2x80x94OCF3, xe2x80x94S(O) nxe2x80x94R6, xe2x80x94N(R2)xe2x80x94S(O)2 (R2), halo, xe2x80x94CF3, or xe2x80x94NO2;
Z is O, S, N(R2)2, or, when M is not present, H.
Y is P or S;
X is O or S; and
R9 is C(R2)2, O or N(R2); and wherein when Y is S, Z is not S; and
R6 is a 5-6 membered saturated, partially saturated or unsaturated carbocyclic or heterocyclic ring system, or an 8-10 membered saturated, partially saturated or unsaturated bicyclic ring system; wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from O, N, S, S(O)n or N(R2); and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from OH, C1-C4 alkyl, xe2x80x94Oxe2x80x94C1-C4 alkyl or xe2x80x94Oxe2x80x94C(O)xe2x80x94C1-C4 alkyl;
R10 is selected from C1 C8 alkyl, C2-C6 alkenyl, C6-C14 aryl or Ht, wherein R10 optionally contains up to three substituents independently selected from xe2x80x94R3, xe2x80x94CN, xe2x80x94SR5, xe2x80x94SOR5, xe2x80x94SO2R5, xe2x80x94SRxe2x80x94NR5xe2x80x94O(O)R6, xe2x80x94NRxe2x80x94(SO2)R5, xe2x80x94C(O)N(R5)2, xe2x80x94C(S)N(R5)2, xe2x80x94S(O)2N(R5)2, xe2x80x94C(O)R6, xe2x80x94C(S)R6, xe2x80x94N(R5)2, xe2x80x94NRxe2x80x94C(O)R5, xe2x80x94NR5xe2x80x94C(O)OR5, xe2x80x94NR5xe2x80x94C(O)N(R5)2, xe2x80x94NR5xe2x80x94C(S)R5, xe2x80x94NR5xe2x80x94C(S)ORxe2x80x94, xe2x80x94NR5xe2x80x94C(S)N(R5)2, xe2x80x94NR5xe2x80x94C[xe2x95x90N(R5)]xe2x80x94N(R5) 2, xe2x80x94NHxe2x80x94O[xe2x95x90Nxe2x80x94NO2]xe2x80x94NH2, xe2x80x94NHxe2x80x94C[xe2x95x90Nxe2x80x94NO2]xe2x80x94OR5, xe2x80x94N(R8)2xe2x80x94C(O)R8, xe2x80x94OC(O)R6, xe2x80x94OC(O)N(R5)2, xe2x80x94OC(S)N(R5)2, wherein any one of the xe2x80x94CH2 groups of said alkyl or alkenyl chains of R10 may be optionally replaced by O, S, SO, SO2, C(O) or NR5;
wherein each R5 is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or Ht, wherein each R5, except for hydrogen, is optionally substituted with xe2x80x94CF3, xe2x80x94PO3R3, azido or halo;
Preferably, at least one R is selected from: 
PO3-spermine, PO3-(spermidine)3 or PO3-(meglamine)2.
It will be understood by those of skill in the art that component M or Mxe2x80x2 in the formulae set forth herein will have either a covalent, a covalent/zwitterionic, or an ionic association with either Z or R9 depending upon the actual choice for M or Mxe2x80x2. When M or Mxe2x80x2 is hydrogen, alkyl, alkenyl, or R6, M or Mxe2x80x2 is covalently bound to R9 or Z. If M is a mono- or bivalent metal or other charged species (i.e., NH4+), there is an ionic interaction between M and Z and the resulting compound is a salt.
When x is 0 in (M)x, Z may be a charged species. When that occurs, the other M may be oppositely charged to produce a 0 net charge on the molecule. Alternatively, the counter ion may located elsewhere in the molecule.
Except where expressly provided to the contrary, as used herein, the definitions of variables A, R1xe2x80x94R4, R6xe2x80x94R9, Ht, B. x, n, D, Dxe2x80x2, M, Q, X, Y, Z and E are to be taken as they are defined above for the compounds of formula I.
According to a preferred embodiment, the compounds of this invention are those represented by formula II, formula III or formula IV: 
wherein A, R3, R7, Ht, D, Dxe2x80x2, x, E are as defined above for compounds of formula I. For ease of reference, the two R3 moieties present in formula IV have been labeled R3 and R3xe2x80x2.
For compounds of formula II, more preferred compounds are those wherein:
A is xe2x80x94C(O)Ht;
Dxe2x80x2 is xe2x80x94Oxe2x80x94R10;
E is C6-C10 aryl optionally substituted with one or more substituents selected from oxo, xe2x80x94OR2, SR2, xe2x80x94R2, xe2x80x94N(R2,)2, xe2x80x94R2xe2x80x94OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)2, xe2x80x94S(O)2xe2x80x94N(R2)2, xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94R2, xe2x80x94C(O)xe2x80x94R2, xe2x80x94S(O)nxe2x80x94R2, xe2x80x94OCF3, xe2x80x94S(O)nxe2x80x94Q, methylenedioxy, xe2x80x94N(R2)xe2x80x94S(O)2 (R2), halo, xe2x80x94CF3, xe2x80x94NO2, Q, xe2x80x94OQ, xe2x80x94OR7, xe2x80x94SR7, xe2x80x94R7, xe2x80x94N(R2)(R7) or xe2x80x94N(R7)2; or a 5-membered heterocyclic ring containing one S and optionally containing N as an additional heteroatom, wherein said heterocyclic ring is optionally substituted with one to two groups independently selected from xe2x80x94CH3, R4, or Ht.
all other variables are as defined for formula I.
Another preferred embodiment for the formula II compounds are those wherein:
E is a 5-membered heterocyclic ring containing one S and optionally containing N as an additional heteroatom, wherein said heterocyclic ring is optionally substituted with one to two groups independently selected from xe2x80x94CH3, R4, or Ht; and
all other variables are as defined for formula I.
More preferred are any of the formula II compounds set forth above, wherein R7 in xe2x80x94OR7 is xe2x80x94PO(OM)2 or C(O)CH2OCH2CH2OCH2CH2OCH3 and both R7 in xe2x80x94N(R7)2 are H, wherein M is H, Li, Na, K or C1-C4 alkyl; or wherein R in xe2x80x94OR is C(O)CH2OCH2CH2OCH3, one R7 in xe2x80x94N(R7)2 is C(O)CH2OCH2CH2OCH3 and the other is H.
According to another preferred embodiment of the present invention, there is provided compounds of formula (V): 
wherein:
A is C6-C14 aryl optionally substituted with one or more groups independently selected from the group consisting of C1-C8 alkyl or hydroxy, or OR4, wherein R4 is C1-C8 alkyl, C3-C7 cycloalkyl, C1-C6 alkyl substituted with C6-C4, C6-C14 aryl optionally substituted with C1-C6 alkyl, heterocyclyl or heterocyclylalkyl;
E is C6-C4 aryl, optionally substituted with one or more groups selected from nitro, oxo, alkoxy, amino, hydroxyamino; heterocyclcyl, optionally substituted with one or more groups selected from the group consisting of nitro, oxo, alkoxy, amino, hydroxyamino or N(CO)OCH3;
R10 and R7 are as defined above; or a pharmaceutically acceptable derivative thereof.
According to yet another preferred embodiment, there is provided compounds of Formula (VI): 
wherein:
R7 and R10 are as defined above for formula I;
E is C6-C4 aryl, optionally substituted with one or more groups selected from the group consisting of nitro, oxo, alkoxy, amino, hydroxyamino; heterocyclcyl, optionally substituted with one or more groups selected from the group consisting of nitro, oxo, alkoxy, amino, hydroxyamino or N(CO)OCH3;
or a pharmaceutically acceptable derivative thereof.
According to yet another preferred embodiment, there is provided a compound of Formula (VII): 
wherein:
A, E, R7 and R10 are as defined in formula (I); or a pharmaceutically acceptable derivative thereof.
According to yet another preferred embodiment, there is provided a compound of formula (VIII): 
wherein A, R1, R3, R7 and E are as defined in formula (I).
According to yet another embodiment of the present invention, there are provided compounds of the formula: 
wherein Xxe2x88x92is a pharmaceutically suitable counterion; 
wherein R10 is selected from isopropyl or cyclopentyl; R11 is selected from NHR7 or OR7; x, R7 and G are as defined above; and Xxe2x88x92is a pharmaceutically acceptable counterion.
The compounds according to the invention contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be of the R or S configuration. Although the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned.
More preferred compounds of formula (I) of the present invention are set forth below in Table 1.
Most preferred compounds of the present invention include the following:
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-((15, 2R)-1-benzyl-3-(cyclopentyloxy)[(3-[2-(dimethylamino)ethyl]aminophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate;
(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yl N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(3-[2-(dimethylamino)ethyl]aminophenyl)sulfonyl]amino-2-hydroxypropyl)carbamate;
(3R,3aS,6aR)Hexahydrofuro[2,3-b]furan-3-yl-N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)(2-[(methylsulfonyl)amino] benzimidazol-5-ylsulfonyl)amino-2-hydroxypropyl)carbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-(15, 2R)-3-[[(3-N-methylaminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate;
1,3-Dioxan-5-yl N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy) (2-{(methoxycarbonyl)amino]-1H-benzimidazol-5-ylsulfonyl) amino]-2-hydroxypropylcarbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-(1S,2R)-1-benzyl-2-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](tetrahydro-2H-pyran-4-yloxy)amino]propylcarbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-(1S,2R)-3-[[(3-aminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl AT-[(1S,2R)-1-benzyl-3-((cyclopentyloxy)[3-(2-[methoxy(methyl)amino]-2-oxoethylamino)phenyllsulfonylamino)-2-hydroxypropyl] carbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-1-benzyl-4-(cyclopentyloxy)-2-hydroxy-4-(6-quinoxalinyl sulfonyl)butyl]carbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-((1S, 2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S, 2R)-1-benzyl-3-((cyclopentyloxy)[3-(2-[(methylsulfonyl)amino] ethylamino)phenyl]sulfonylamino)-2-hydroxypropyl]carbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-(1S,2R)-3-[[(3-N-methylaminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate phosphate ester;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-(1S,2R)-3-[[(3-aminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate phosphate ester;
(3R,3aS,6aR) hexahydrofuro [2,3-b]furan-3-yi N-(1S,2R)-3-[[(4-aminophenyl)sulfonyl](cyclopentyloxy)amino]-1-benzyl-2-hydroxypropyl carbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(4-hydroxyphenyl)sulfonyl]amino}-2-hydroxypropylcarbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(1-ethylpropoxy)amino]-1-benzyl-2-hydroxypropylcarbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(cyclopentyloxy)amino]-1-benzyl-2-(phosphonooxy)propyl]carbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(cyclohexyloxy)amino]-1-benzyl-2-hydroxypropylcarbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl 3-[(1,3-benzodioxol-5-ylsulfonyl)(tetrahydro-2H-pyran-4-yloxy)amino]-1-benzyl-2-hydroxypropylcarbamate;
(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(cyclopentyloxy)amino]-1-benzyl-2-(phosphonooxy)propyl]carbamate; or a pharmaceutically acceptable derivative thereof.
The compounds of the present invention can be readily prepared by techniques known in the art. Scheme I illustrates a general synthetic route to compounds of formula (V), a preferred sub-genus of formula (I).
According to Scheme I, commercially available N-hydroxyphthalimide is reacted with R10 -Br or R10 OH under displacement or Mitsonobu-type conditions respectively, followed by hydrazinolysis in ethanol to produce the amine of formula (I). Amine of formula (I) is further utilized in two synthetic routes, Path 1 and Path 2.
Path 1
Step 1: Amine of formula (I) is reacted with a sulfonyl chloride of formula (A) to produce sulfonamide of formula (IIxe2x80x2).
Step 2: Sulfonamide of formula (IIxe2x80x2) is reacted with intermediate of formula (B), which bears an amine protecting group P, such as t-butoxycarbonyl, to produce compound of formula (IIIxe2x80x2). Suitable amine protecting groups are described in numerous references, including T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser""s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995). Examples of such amino protecting groups include, but are not limited to, Cbz or Alloc.
Step 3: Compound of formula (IIIxe2x80x2) is then reacted with A-L, wherein L is a leaving group, to produce compound of formula (IV). A leaving group is an atom or group which is displaceable upon reaction with an appropriate amine or sulfonamide. Suitable leaving groups would be obvious to one of skill in the art and include but are not limited to hydroxyls, carboxylates and halides. 
Step 4: Compound of formula (IV) is then converted to compound of formula (V) by functional transformation of the hydroxy group.
Path 2 differs from Path 1 only in the sequence of reagents employed to convert compound of formula (I) to compound of formula (IV).
The synthetic approach illustrated in Scheme I can be readily extended to produce other compounds of the present invention. The above synthetic scheme is not intended to comprise a comprehensive list of all means by which compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art.
As discussed above, the novel compounds of the present invention are excellent ligands for aspartyl proteases, particularly HIV-1 and HIV-2 proteases. Accordingly, these compounds are capable of targeting and inhibiting late stage events in HIV replication, i.e., the processing of the viral polyproteins by HIV encoded proteases. Such compounds inhibit the proteolytic processing of viral polyprotein precursors by inhibiting aspartyl protease. Because aspartyl protease is essential for the production of mature virions, inhibition of that processing effectively blocks the spread of virus by inhibiting the production of infectious virions, particularly from chronically infected cells. Compounds according to this invention advantageously inhibit the ability of the HIV-1 virus to infect immortalized human T cells over a period of days, as determined by an assay of extracellular p24 antigenxe2x80x94a specific marker of viral replication. Other anti-viral assays have confirmed the potency of these compounds.
The compounds of this invention may be employed in a conventional manner for the treatment of viruses, such as HIV and HTLV, which depend on aspartyl proteases for obligatory events in their life cycle. Such methods of treatment, their dosage levels and requirements may be selected by those of ordinary skill in the art from available methods and techniques. For example, a compound of this invention may be combined with a pharmaceutically acceptable adjuvant for administration to a virally-infected patient in a pharmaceutically acceptable manner and in an amount effective to lessen the severity of the viral infection.
Alternatively, the compounds of this invention may be used in vaccines and methods for protecting individuals against viral infection over an extended period of time. The compounds may be employed in such vaccines either alone or together with other compounds of this invention in a manner consistent with the conventional utilization of Eprotease inhibitors in vaccines. For example, a compound of this invention may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period time against HIV infection. As such, the novel protease inhibitors of this invention can be administered as agents for treating or preventing HIV infection in a mammal.
The compounds of formula I, especially those having a molecular weight of less than about 700 g/mole, may be readily absorbed by the bloodstream of mammals upon oral administration. Compounds of formula I having a molecular weight of less than about 600 g/mole are most likely to demonstrate oral availability. This surprisingly impressive oral availability makes such compounds excellent agents for orally-administered treatment and prevention regimens against HIV infection.
The compounds of this invention may be administered to a healthy or HIV-infected patient either as a single agent or in combination with other anti-viral agents which interfere with the replication cycle of HIV. By administering the compounds of this invention with other anti-viral agents which target different events in the viral life cycle, the therapeutic effect of these compounds is potentiated. For instance, the co-administered anti-viral agent can be one which targets early events in the life cycle of the virus, such as cell entry, reverse transcription and viral DNA integration into cellular DNA. Anti-HIV agents targeting such early life cycle events include, didanosine (ddI), alcitabine (ddC), d4T, zidovudine 3AZT), polysulfated polysaccharides, sT4 (soluble CD4), 3TC, 935U83, 1592U89, 524W91, ganciclovir, dideoxycytidine, trisodium phosphonoformate, eflornithine, ribavirin, acyclovir, alpha interferon and trimenotrexate. Ribonucleotide reductase inhibitors such as hydroxyurea may also be used. Additionally, non-nucleoside inhibitors of reverse transcriptase, such as TIBO, delavirine (U90) or nevirapine, may be used to potentiate the effect of the compounds of this invention, as may viral uncoating inhibitors, inhibitors of trans-activating proteins such as tat or rev, or inhibitors of the viral integrase.
Combination therapies according to this invention exert a synergistic effect in inhibiting HIV replication because each component agent of the combination acts on a different site of HIV replication. The use of such combinations also advantageously reduces the dosage of a given conventional anti-retroviral agent which would be required for a desired therapeutic or prophylactic effect as compared to when that agent is administered as a monotherapy. These combinations may reduce or eliminate the side effects of conventional single anti-retroviral agent therapies while not interfering with the anti-retroviral activity of those agents. These combinations reduce potential of resistance to single agent therapies, while minimizing any associated toxicity. These combinations may also increase the efficacy of the conventional agent without increasing the associated toxicity. In particular, we have discovered that these compounds act synergistically in preventing the replication of HIV in human T cells. Preferred combination therapies include the administration of a compound of this invention with AZT, ddI, ddC or d4T.
Alternatively, the compounds of this invention may also be co-administered with other HIV protease inhibitors such as Agenerase (VX-478, Vertex), saquinavir, Ro 31-8959 (Roche), L-735,524 (Merck), XM 323 (Du-Pont Merck) A-80,987 (Abbott), MK 639 (Merck), ABT 538 (A-80538, Abbott), AG 1343(Agouron), XM 412 (Du-Pont Merck), XM 450 (Du-Pont Merck), BMS 186318 (Bristol-Meyers Squibb), ABT 378 (Abbott) and CPG 53,437 (Ciba Geigy) to increase the effect of therapy or prophylaxis against various viral mutants or members of other HIV quasi species.
We prefer administering the compounds of this invention as single agents or in combination with retroviral reverse transcriptase inhibitors, such as derivatives of AZT, or other HIV aspartyl protease inhibitors. We believe that the co-administration of the compounds of this invention with retroviral reverse transcriptase inhibitors or HIV aspartyl protease inhibitors may exert a substantial synergistic effect, thereby preventing, substantially reducing, or completely eliminating viral infectivity and its associated symptoms.
The compounds of this invention can also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diethyldithiocarbamate, tumor necrosis factor, naltrexone, tuscarasol and rEPO); and antibiotics (e.g., pentamidine isethiorate) to prevent or combat infection and disease associated with HIV infections, such as AIDS and ARC.
When the compounds of this invention are administered in combination therapies with other agents, they may be administered sequentially or concurrently to the patient. Alternatively, pharmaceutical or prophylactic compositions according to this invention may be comprised of a combination of an aspartyl protease inhibitor of this invention and another therapeutic or prophylactic agent.
Although this invention focuses on the use of the compounds disclosed herein for preventing and treating HIV infection, the compounds of this invention can also be used as inhibitory agents for other viruses which depend on similar aspartyl proteases for obligatory events in their life cycle. These viruses include, as well as other AIDS-like diseases caused by retroviruses, such as simian immunodeficiency viruses, but are not limited to, HTLV-I and HTLV-II. In addition, the compounds of this invention may also be used to inhibit other aspartyl proteases, and in particular, other human aspartyl proteases, including renin and aspartyl proteases that process endothelin precursors. Pharmaceutical compositions of this invention comprise any of the compounds of the present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. We prefer oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as Ph. Helv or a similar alcohol.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, preferably between about 0.5 and about 50 mg/kg body weight per day of the active ingredient compound are useful in the prevention and treatment of viral infection, including HIV infection. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Preferably, such preparations contain from about 20% to about 80% active compound.
Upon improvement of a patient""s condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
As the skilled artisan will appreciate, lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the infection, the patient""s disposition to the infection and the judgment of the treating physician.
The compounds of this invention are also useful as commercial reagents which effectively bind to aspartyl proteases, particularly HIV aspartyl protease. As commercial reagents, the compounds of this invention, and their derivatives, may be used to block proteolysis of a target peptide or may be derivatized to bind to a stable resin as a tethered substrate for affinity chromatography applications. These and other uses which characterize commercial aspartyl protease inhibitors will be evident to those of ordinary skill in the art.
As used herein, the compounds according to the invention are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. A xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d or xe2x80x9cpharmaceutically acceptable prodrugxe2x80x9d means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an inhibitorily active metabolite or residue thereof. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
The compounds according to the invention may be used in the form of salts derived from inorganic or organic acids. Included among such acid salts, for example, are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectianate, persulfate, phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g., magnesium), ammonium and +NW4 (wherein W is Cl-4 alkyl). Physiologically acceptable salts of a hydrogen atom or an amino group include salts or organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+, NH4 +, and NW4 +(wherein W is a C1-4 alkyl group)
Pharmaceutically acceptable salts include salts of organic carboxylic acids such as ascorbic, acetic, citric, lactic, tartaric, malic, maleic, isothionic, lactobionic, p-aminobenzoic and succinic acids; organic sulphonic acids such as methanesulphonic, ethanesulphonic, benzenesulphonic and p-toluenesulphonic acids and inorganic acids such as hydrochloric, sulphuric, phosphoric, sulphamic and pyrophosphoric acids.
For therapeutic use, salts of the compounds according to the invention will be pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
Preferred salts include salts formed from hydrochloric, sulfuric, acetic, succinic, citric and ascorbic acids.
Preferred esters of the compounds according to the invention are independently selected from the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, C1-4alkyl, or C1-4alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C6-24)acyl glycerol.
In such esters, unless otherwise specified, any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms, Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group.
Any reference to any of the above compounds also includes a reference to a pharmaceutically acceptable salts thereof.
The compounds according to the invention are especially useful for the treatment of AIDS and related clinical conditions such as AIDS related complex (ARC), progressive generalized lymphadenopathy (PGL), Kaposi""s sarcoma, thrombocytopenic purpura, AIDS-related neurological conditions such as AIDS dementia complex, multiple sclerosis or tropical paraperesis, and also anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.
In a further aspect of the invention there are provided the compounds according to the invention for use in medical therapy particularly for the treatment or prophylaxis of viral infections such as HIV infections.
According to another aspect, the present invention provides a method for the treatment or prevention of the symptoms or effects of a viral infection in an infected animal, for example, a mammal including a human, which comprises treating said animal with a therapeutically effective amount of a compound according to the invention. According to a particular embodiment of this aspect of the invention, the viral infection is an HIV infection. A further aspect of the invention includes a method for the treatment or prevention of the symptoms or effects of an HBV infection.
The compounds according to the invention may also be used in adjuvant therapy in the treatment of HIV infections or HIV-associated symptoms or effects, for example Kaposi""s sarcoma.
The present invention further provides a method for the treatment of a clinical condition in an animal, for example, a mammal including a human which clinical condition includes those which have been discussed in the introduction hereinbefore, which comprises treating said animal with a therapeutically effective amount of a compound according to the invention. The present invention also includes a method for the treatment or prophylaxis of any of the aforementioned infections or conditions.
In yet a further aspect, the present invention provides the use of a compound according to the invention in the manufacture of a medicament for the treatment or prophylaxis of any of the above mentioned viral infections or conditions. It will be appreciated that of compounds of Formula (I), (II), (III), (IV), and (V) and one or more other HIV protease inhibitors, reverse transcriptase inhibitors, or non-nucleoside reverse transcriptase inhibitors may be used in the manufacture of the above medicament.
Reference herein to treatment extends to prophylaxis as well as the treatment of established infections or symptoms.
The above compounds according to the invention and their pharmaceutically acceptable derivatives may be employed in combination with other therapeutic agents for the treatment of the above infections or conditions. Combination therapies according to the present invention comprise the administration of at least one compound of the formula (I) or a pharmaceutically acceptable derivative thereof and at least one other pharmaceutically active ingredient. The active ingredient(s) and pharmaceutically active agents may be administered simultaneously in either the same or different pharmaceutical formulations or sequentially in any order. The amounts of the active ingredient(s) and pharmacuetically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Preferably the combination therapy involves the administration of one compound according to the invention and one of the agents mentioned herein below.
Examples of such further therapeutic agents include agents that are effective for the treatment of viral infections or associated conditions such as (1 alpha, 2 beta, 3 alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine [(-)BHCG, SQ-34514], oxetanocin-G (3,4-bis-(hydroxymethyl)-2-oxetanosyl]guanine), acyclic nucleosides (e.g. acyclovir, valaciclovir, famciclovir, ganciclovir, penciclovir), acyclic nucleoside phosphonates (e.g. (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC), ribonucleotide reductase inhibitors such as 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl) thiocarbonohydrazone, 3xe2x80x2azido-3xe2x80x2-deoxythymidine, hydroxyurea, other 2xe2x80x2,3xe2x80x2-dideoxynucleosides such as 2xe2x80x2, 3xe2x80x2-dideoxycytidine, 2xe2x80x2,3xe2x80x2-dideoxyadenosine, 2xe2x80x2, 3xe2x80x2-dideoxyinosine, 2xe2x80x2,3xe2x80x2-didehydrothymidine, protease inhibitors such as agenerase, indinavir, ritonavir, nelfinavir, [3S-[3R*(1R*, 2S*)]]-[3[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro-3-furanyl ester (141W94), oxathiolane nucleoside analogues such as (-)-cis-1-(2-hydroxymethyl)-1,3-oxathiolane 5-yl)-cytosine (lamivudine) or cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC), 3xe2x80x2-deoxy-3xe2x80x2-fluorothymidine, 5-chloro-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-fluorouridine, (-)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, ribavirin, 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G), tat inhibitors such as 7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2-(H)one (Ro5-3335), 7-chloro-1,3-dihydro-5-(1H-pyrrcl-2yl)-3H-1,4-benzodiazepin-2-amine (Ro24-7429), interferons such as a-interferon, renal excretion inhibitors such as probenecid, nucleoside transport inhibitors such as dipyridamole; pentoxifylline, N-acetylcysteine (NAC), Procysteine, xcex1-trichosanthin, phosphonoformic acid, as well as immunomodulators such as interleukin II or thymosin, granulocyte macrophage colony stimulating factors, erythropoetin, soluble CD4 and genetically engineered derivatives thereof, or non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine (BI-RG-587), loviride (xcex1-APA) and delavuridine (BHAP), and phosphonoformic acid, and 1,4-dihydro-2H-3,1-benzoxazin-2-ones NNRTIs such as (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (L-743,726 or DMP-266), and quinoxaline NNRTIs such as isopropyl (2S)-7-fluoro-3,4-dihydro-2-ethyl-3-oxo-1(2H)-quinoxalinecarboxylate (HBY1293).
More preferably the combination therapy involves the administration of one of the above mentioned agents and a compound within one of the preferred or particularly preferred sub-groups within formula (I) as described above. Most preferably the combination therapy involves the joint use of one of the above named agents together with one of the compounds of formula (I) specifically named herein.
The present invention further includes the use of a compound according to the invention in the manufacture of a medicament for simultaneous or sequential administration with at least one other therapeutic agent, such as those defined hereinbefore.
In order that this invention may be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.